Galactokinase Deficiency 

  • Author: Karl S Roth, MD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Sep 2, 2009
 

Background

As with all hexose sugars, metabolism of ingested galactose requires an initial phosphorylation of the molecule using adenosine triphosphate (ATP). Unlike the metabolism of glucose, which ordinarily depends on the activity of hexokinase with a wide substrate-specificity to carry out this reaction, substrate-specific galactokinase activity exclusively phosphorylates galactose.[1]

In 1965, galactokinase deficiency was first identified in a patient who presented with cataracts and galactosuria that developed upon drinking milk. The concurrence of cataracts and galactosuria in a single individual suggested the possibility of a new type of galactosemia. This presentation differed from that of classic galactosemia in many important aspects; neither hepatosplenomegaly nor signs of mental retardation were present. When the researchers realized that the patient did not accumulate galactose-1-phosphate despite the accumulated galactose, the patient's underlying defect was deduced as the lack of the enzyme mediating 1-phosphorylation of galactose.

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Pathophysiology

UDP-galactose synthesis and galactosemia. The mostUDP-galactose synthesis and galactosemia. The most common form of galactosemia is due to a deficiency of galactose-1-phosphate uridyltransferase (GALT). This enzyme normally uses galactose-1-phosphate derived from dietary galactose. In the absence of GALT, galactose-1-phosphate accumulates, along with excessive galactose and its oxidative and reductive products galactitol and galactonate (not shown). UDP-galactose synthesis may also be impaired in the absence of GALT but not completely because UDP-galactose-4′-epimerase (GALE) can form UDP-galactose from UDP-glucose and can supply the donor to galactosyltransferases required for normal glycoconjugate biosynthesis.

An appreciation of the differences between the enzyme deficiencies and their clinical manifestations is key to understanding the pathophysiology of galactokinase and galactose-1-phosphate uridyltransferase galactosemias. Whereas vomiting, failure to thrive, jaundice, hepatomegaly, and cataracts are characteristic of the onset of transferase-deficient galactosemia, cataract development is usually the only symptom observed in an infant with kinase deficiency. In people with transferase-deficient galactosemia, galactose-1-phosphate accumulates; in those with kinase deficiency, galactose-1-phosphate cannot be produced. Galactose-1-phosphate is assumed to be the substance that causes the devastating manifestations seen in people with classic galactosemia. Note that this assumption lacks definitive proof despite the intrinsic and compelling logic.

In contrast, the mechanism that produces galactose-related cataracts is understood fairly well. The lens of the eye contains the aldose reductase enzyme. When presented with accumulated galactose, this enzyme reduces the aldehydic end group and produces galactitol, the analogous sugar alcohol. This compound exerts osmotic pressure within the lens because it slowly diffuses. While the induced lenticular swelling is not solely responsible for subsequent cataract formation, most researchers believe that the inciting event is galactitol rather than galactose-1-phosphate accumulation. The evidence favors this view because patients with galactokinase deficiency who cannot produce galactose-1-phosphate still form cataracts.

While patients who are deficient in galactokinase accumulate galactitol in the liver at rates comparable to those with transferase-deficient galactosemia, only the latter display evidence of hepatic damage. Hence, much remains to be learned about the pathophysiologic implications of galactose metabolic impairment.

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Epidemiology

Frequency

United States

Because most newborn screening programs are designed to identify transferase deficiency, accumulated galactose in submitted blood samples is missed. Accordingly, the data are insufficient to provide an accurate assessment of prevalence, although the estimated range is 1 per 50,000-100,000 live births.

International

The prevalence among certain Eastern European populations, in particular the Romani (Gypsy) population, is estimated to be approximately 1 per 10,000. The Romani people generally possess a mutation known as P28T, considered the founder mutation.

Mortality/Morbidity

The literature indicates no risk of mortality. Morbidity is limited to cataract formation in untreated individuals, although rare cases of pseudotumor cerebri have been reported. Both resolve with effective therapy. Mental retardation and hepatic damage are not associated with galactokinase deficiency.

Sex

As an autosomal recessive condition, the disorder is distributed equally between sexes.

Age

Because galactokinase deficiency is a genetic disease, it is present from conception and may be discovered at birth through the presence of congenital cataracts.

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Contributor Information and Disclosures
Author

Karl S Roth, MD  Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research

Disclosure: MDS Pharma Salary Employment

Specialty Editor Board

Michael Fasullo, PhD  Senior Scientist, Ordway Research Institute; Associate Professor, State University of New York at Albany; Adjunct Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College

Michael Fasullo, PhD is a member of the following medical societies: American Society for Biochemistry and Molecular Biology and Radiation Research Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

Hagop Youssoufian, MD, MSc  Vice President of Clinical Research, ImClone Systems Incorporated

Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References
  1. Cuthbert C, Klapper H, Elsas L. Diagnosis of inherited disorders of galactose metabolism. Curr Protoc Hum Genet. Jan 2008;Chapter 17:Unit 17.5. [Medline].

  2. Park HD, Kim YK, Park KU, Kim JQ, Song YH, Song J. A novel c.-22T>C mutation in GALK1 promoter is associated with elevated galactokinase phenotype. BMC Med Genet. Mar 24 2009;10:29. [Medline].

  3. Berry GT. The role of polyols in the pathophysiology of hypergalactosemia. Eur J Pediatr. 1995;154(7 Suppl 2):S53-64. [Medline].

  4. Beutler E, Matsumoto F, Kuhl W, Krill A, Levy N, Sparkes R, et al. Galactokinase deficiency as a cause of cataracts. N Engl J Med. Jun 7 1973;288(23):1203-6. [Medline].

  5. Bosch AM, Bakker HD, van Gennip AH, van Kempen JV, Wanders RJ, Wijburg FA. Clinical features of galactokinase deficiency: a review of the literature. J Inherit Metab Dis. Dec 2002;25(8):629-34. [Medline].

  6. Gitzelmann R. Hereditary galactokinase deficiency, a newly recognized cause of juvenile cataracts. Pediatr Res. 1967;1:14-23.

  7. Hunter M, Heyer E, Austerlitz F. The P28T mutation in the GALK1 gene accounts for galactokinase deficiency in Roma(Gypsy) patients across Europe. Pediatr Res. 2002;51:602-606.

  8. Kerr MM, Logan RW, Cant JS, Hutchison JH. Galactokinase deficiency in a newborn infant. Arch Dis Child. Dec 1971;46(250):864-6. [Medline].

  9. Levy NS, Krill AE, Beutler E. Galactokinase deficiency and cataracts. Am J Ophthalmol. Jul 1972;74(1):41-8. [Medline].

  10. Pickering WR, Howell RR. Galactokinase deficiency: clinical and biochemical findings in a new kindred. J Pediatr. Jul 1972;81(1):50-5. [Medline].

  11. Reich S, Hennerman J, Vetter B. An unexpectedly high frequency of hypergalactosemia in an immigrant Bosnian population revealed by newborn screening. Pediatr Res. 2002;51:598-601.

  12. Sangiuolo F, Magnani M, Stambolian D. Biochemical characterization of two GALK1 mutations in patients with galactokinase deficiency. Hum Mutat. 2004;23:396.

  13. Thalhammer O, Gitzelmann R, Pantlitschko M. Hypergalactosemia and galactosuria due to galactokinase deficiency in a newborn. Pediatrics. Sep 1968;42(3):441-5. [Medline].

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UDP-galactose synthesis and galactosemia. The most common form of galactosemia is due to a deficiency of galactose-1-phosphate uridyltransferase (GALT). This enzyme normally uses galactose-1-phosphate derived from dietary galactose. In the absence of GALT, galactose-1-phosphate accumulates, along with excessive galactose and its oxidative and reductive products galactitol and galactonate (not shown). UDP-galactose synthesis may also be impaired in the absence of GALT but not completely because UDP-galactose-4′-epimerase (GALE) can form UDP-galactose from UDP-glucose and can supply the donor to galactosyltransferases required for normal glycoconjugate biosynthesis.
 
 
 
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